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`www.medscape.com
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`T-DM1: Golden Age in HER2+ Breast Cancer?
`June 12, 2012
`Kathy D. Miller, MD, Harold J. Burstein, MD, PhD
`
`Introductions
`
`Kathy D. Miller, MD: Hello. I am Kathy Miller, Associate Professor of Medicine at Indiana University School of
`Medicine at Indianapolis. Welcome to Medscape Oncology Insights on Breast Cancer, coming to you today from the
`2012 annual meeting of the American Society of Clinical Oncology (ASCO®). Joining me today is Dr. Hal Burstein,
`Associate Professor at Harvard Medical School and Medical Oncologist at Dana-Farber Cancer Institute in Boston.
`Welcome, Hal.
`
`Harold J. Burstein, MD, PhD: Hi, Kathy. How are you?
`
`Dr. Miller: I'm great. So tell me, when you think about breast cancer at ASCO® 2012, what comes to mind?
`
`The Big Story: T-DM1
`
`Dr. Burstein: The big story here is the data for trastuzumab emtansine (T-DM1). Part of the plenary session this
`afternoon is the so-called EMILIA trial,[1] which is the registrational study for T-DM1.This is a very interesting drug
`because it is an antibody/drug conjugate. Part of the excitement is the data themselves, and another part of the
`excitement is the fact that this is really the first widely used indication for this whole new class of drugs.
`
`So, what is an antibody/drug conjugate? It is the traditional antibody -- in this case, trastuzumab -- that has been
`chemically linked to a lethal poison called a maytansinoid chemotherapy. By using a very low dose of the
`chemotherapy, which is linked to this antibody, they can deliver the toxin -- boom -- right to the tumor. We are seeing
`incredible data.
`
`What is exciting about this class of drugs is that there are literally dozens of related products now in clinical
`development, and they hold the promise of giving tremendous cancer treatment without the traditional side effects of
`chemotherapy.
`
`Dr. Miller: Oncologists who treat patients with lymphoma are probably aware that this is not the first in class of
`antibody/drug conjugate. They have seen data in refractory lymphoma and refractory Hodgkin disease using the
`same strategy with an antibody complex linked to chemotherapy that shows substantial single-agent activity in
`previously treated lymphoma patients and previous bone marrow transplant patients.
`
`Dr. Burstein: You caught me out. You are technically correct, that there is already a US Food and Drug
`Administration (FDA)-approved drug in this class. But for most medical oncologists, treatment for extensively
`refractory lymphoma or refractory Hodgkin disease -- which is the indication for this other product -- is very
`uncommon. So the first antibody/drug conjugate that most oncologists are actually going to prescribe to patients and
`use on a regular day-to-day basis is likely to be T-DM1.
`
`Dr. Miller: This agent is clearly less toxic, but is it also more effective?
`
`EMILIA: Longer Survival, Fewer Toxicities
`
`Dr. Burstein: That is the core of the EMILIA trial. EMILIA is a study for patients with human epidermal growth factor
`receptor 2 (HER2)-positive advanced breast cancer. To be eligible for the study, patients were required not only to
`have HER2-positive disease but also to have been previously treated with trastuzumab and chemotherapy. The
`randomization was to the current FDA-approved regimen of capecitabine and lapatinib, another targeted
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`combination regimen, vs T-DM1. The principal endpoint was originally progression-free survival. The study was
`modified midway through to make it larger and to look at overall survival as well.
`
`The data suggest that there is a dramatic difference in progression-free survival favoring T-DM1, and there is an
`emerging difference in overall survival. Actually, it looks like a clinically compelling difference in overall survival. The
`P value is approximately .0005, but because of the way they parceled out alpha, there are some questions about
`whether it met its statistical endpoint. That is unlikely to be a real issue because when you look at the data, they are
`surprisingly positive. This is going to be a very widely accepted drug within a short period.
`
`So, the drug has better efficacy and longer tumor control, and the beauty of it is, it doesn't produce the
`chemotherapy-type side effects. In the comparison arm, the major side effects were the risks for hand/foot syndrome
`and diarrhea, but none of that occurred with T-DM1. With long-term exposure to T-DM1, you see some cumulative
`thrombocytopenia, which is rarely clinically significant. You also see some fatigue and transaminitis.
`
`Here is another big plus for T-DM1: It doesn't make the hair fall out. This is a very different kind of therapy, much
`better tolerated and more active than some of our existing options for trastuzumab-refractory HER2-positive breast
`cancer. Right now, this drug is the golden era of research in HER2-driven disease.
`
`Targeting Delivery, Not Just a Molecule
`
`Dr. Miller: It is also a golden era for the approach of targeting delivery, rather than just targeting a molecule.
`
`Dr. Burstein: That is exactly right. We have expected the existing antibodies that we have used in oncology not just
`to reach the tumor cell, but to actually tweak the tumor cell and do something. The great examples are rituximab and
`trastuzumab. When you start to think about using antibodies as a delivery system, however, all you have to do is get
`the antibody to "take you to the right address." You can rely on the toxin to do the heavy lifting, and that rapidly
`broadens its ability. It is pretty easy to make antibodies that bind to cancer cells. What is hard is to make them bind
`to cancer cells and do something.
`
`The use of antibodies as delivery vehicles -- you are going to see an explosion of interest in this. There are many
`compelling layers to this treatment. You need a good antibody; a good, well-tolerated toxin; and a linker that allows
`the toxin to liberate itself from the antibody and go after the cancer cell. It's not a trivial problem, but it's an exciting
`one.
`
`Dr. Miller: It is one that looks solvable from the first 2 agents we have in this class.
`
`Dr. Burstein: The technology has been there for a couple of decades, but it has taken a long time to see it come to
`fruition.
`
`Chemotherapy: How to Do It Better
`
`Dr. Miller: I want to take you back to some older topics, because we still have a lot of chemotherapy questions. At
`least for the next several years, chemotherapy even in the setting of HER2-positive disease is going to be part of our
`treatment armamentarium. Several studies looked at whether we could do better with our existing chemotherapy
`drugs.
`
`Dr. Burstein: You are exactly right. The sexy stuff in breast cancer is all about HER2-targeted biologics, but that is
`only 15%-20% of breast cancer. For the other 80%-85% of patients, we still rely on chemotherapy for a lot of
`important tasks. Several important comparative studies, one in the metastatic setting and one in the adjuvant setting
`from the Cooperative Groups, looked to see whether we could improve how we used chemotherapy.
`
`Dr. Miller: What is the short answer?
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`Dr. Burstein: The short answer is that the old ways still look pretty good. Old friends are good ones, and they hold
`up well. CALBG 40502, led by Hope Rugo,[2] compared weekly paclitaxel vs weekly nab-paclitaxel vs weekly
`ixabepilone (almost all given with bevacizumab because of the way the study was set up) as first-line treatment for
`advanced breast cancer. The patients typically had HER2-negative tumors because they weren't getting a targeted
`therapy.
`
`In terms of safety, tolerability, and efficacy, weekly paclitaxel was the winner. Questions might remain about whether
`the investigators dosed the nab-paclitaxel excessively, because there was a lot of neuropathy. Giving it with the
`ixabepilone-weekly strategy might not be the best way to administer the drug. But certainly, everything points to
`weekly paclitaxel being the big winner. Obviously, we have had a lot of experience with that as the backbone of
`ECOG 2100,[3] and that is going to be the mainstay of our approach for first-line metastatic disease.
`
`Finding the Sweet Spot
`
`Dr. Miller: It also tells us that we can't continue to look at toxicity and efficacy as 2 separate buckets. There is
`interplay between them. Another trial that will probably not get as much play in the United States is a trial from a
`Korean group[4] looking at maintenance chemotherapy in the metastatic setting. It is a bit odd to us, because we
`would typically treat patients until progression or toxicity or some personal reason for that patient to stop therapy.
`But in many parts of the world, patients receive a fairly arbitrary number of cycles. If the patient is responding,
`therapy is stopped. Patients are off treatment until they progress.
`
`The study looked at longer durations of therapy in maintenance found improvements in progression-free survival
`and in overall survival. To do that, however, you need to find that sweet-spot balance between an effective drug and
`a tolerable drug. When you look at the CALGB study, that is where the 2 new, sexier chemotherapy agents faltered.
`
`Dr. Burstein: You are exactly right about the differences in cultural trends and how we use these drugs. The
`Europeans typically give 4-6 months of chemotherapy for advanced breast cancer, and then historically have
`paused to see what happened. The US oncology community tends to treat all patients until progression.
`
`There were some classic trials from the Piedmont Oncology Group 20 years ago, which didn't suggest that
`maintenance or ongoing chemotherapy helped that much. The Spanish trial raises this question again. There was a
`suggestion of a survival difference, but the trade-off was a reduction in quality of life. So we will have to think about
`and weigh these factors with our patients. Perhaps now that we have many more drugs available to us, many of
`which are better tolerated, it's a question that should be asked again in the United States.
`
`Optimal Regimen for Adjuvant Therapy?
`
`Dr. Miller: Particularly in the United States, we spend a lot of time arguing among our colleagues in different
`Cooperative Groups about the optimal third-generation regimen in the adjuvant setting. Several trials have now
`compared third-generation regimens, but they haven't ended the argument. We saw the results from yet another one
`this year: the NSABP B-38 trial.[5] Are the arguments going to continue?
`
`Dr. Burstein: Not in my mind, but you never know what you are going to get into in a bar fight. In the NSABP B38
`study for node-positive breast cancer patients, they compared cyclophosphamide (AC) followed by paclitaxel (ACP,
`or ACT) vs ACT, piggybacking on some gemcitabine, vs the docetaxel, adriamycin, cyclophosphamide regimen
`(TAC), which is familiar to almost everybody in the audience.
`
`Dr. Miller: We should be clear that the ACT or the ACT with gemcitabine was dose-dense.
`
`Dr. Burstein: That's correct. It was the every-2-week regimen that the CALGB had piloted. In that study, adding the
`gemcitabine did not improve on ACT alone. And the results for TAC vs ACT were essentially the same in terms of
`clinical efficacy, but most of the quality of life and toxicity experience suggests that AC followed by paclitaxel is an
`easier regimen to give. My core regimen is AC followed by paclitaxel. It has been very hard to beat that.
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`Studies have now looked at adding gemcitabine, and others have looked at adding capecitabine, and that looks like
`a winner. We had a related study[6] looking at the FAC (5-fluorouracil, doxorubicin, and cyclophosphamide) regimen
`with or without paclitaxel, and there, too, the addition of paclitaxel looked to be beneficial. Right now, the core
`regimen for adjuvant therapy is AC followed by paclitaxel, and I don't see many compelling reasons to try anything
`else.
`
`To Bisphosphonate or Not to Bisphosphonate?
`
`Dr. Miller: One of the other issues that has come up frequently, and has been cause for a lot of arguments in the
`field in the adjuvant setting, is "to bisphosphonate or not to bisphosphonate." We have seen more data and more
`meta-analysis trying to parse subsets in this area, with particular interest shown, perhaps, in the estrogen-deprived
`patients, the postmenopausal patients on an aromatase inhibitor, or the premenopausal patients who get ovarian
`suppression. Are you swayed by the most recent parsing?
`
`Dr. Burstein: I'm still trying to understand the literature well enough to feel strongly one way or the other. In the
`modern era, several reports have now looked at adjuvant bisphosphonates, such as zoledronic acid or clodronate.
`We saw some of this in the past year. For the most part, the aggregate results of the top-line studies have been
`negative. The one exception is the ABCSG-12 trial,[7] which gave ovarian suppression and endocrine therapy with
`tamoxifen or an aromatase inhibitor, with or without zoledronic acid, to young women who were not receiving
`chemotherapy. That study still shows a survival advantage favoring zoledronic acid.
`
`But the AZURE trial,[8] which had a very similar design, using zoledronic acid or not in a larger group of patients, did
`not show a survival advantage. So, people have been trying to figure out whether meta-analysis or subset analysis
`could help us. What we saw at this meeting was a subset analysis from AZURE, which suggested that the older,
`probably postmenopausal, women were most likely to benefit from bisphosphonates.
`
`The argument is that perhaps there is an interaction between the estrogen environment and the role of
`bisphosphonates in promoting bone health, or in some other way that affects the hormonal milieu such that the
`cancers are less likely to grow. At the moment, I find myself intrigued, but not persuaded, by these data. I wish that
`we could have a cleaner analysis. The investigators didn't look at estrogen levels. They used age and menopausal
`status as surrogates for estrogen level in the same way as in the ABCSC-12 trial. They presumed that all these
`women had low estrogen levels because they received ovarian suppression with the gonadotropin-releasing
`hormone agonist, but we don't actually know that.
`
`The verdict is still out. Having said that, we are becoming much more aware of the importance of bone health and
`checking bone density every year or 2, and our threshold for initiating treatment in women who are estrogen-
`deprived probably gets lower in part because we are thinking about this more.
`
`Dr. Miller: We may be cheating a little -- perhaps not willing to say, "Yes, I am doing this for adjuvant therapy," but
`maybe looking for a better reason to give bisphosphonates. And if it helps in the adjuvant setting, that's a bonus.
`
`Dr. Burstein: We are always trying to weigh benefits, risks, and trade-offs. If you can tilt things a little bit one way or
`the other, it makes you feel better about the choices.
`
`Dr. Miller: Thank you, Hal, and thanks to you, our audience, for joining us in this edition of Medscape Oncology
`Insights. This is Kathy Miller, at ASCO® 2012.
`
`References
`
`1. Blackwell KL, Miles D, Gianni L, et al. Primary results from EMILIA, a phase III study of trastuzumab
`emtansine (T-DM1) versus capecitabine (X) and lapatinib (L) in HER2-positive locally advanced or metastatic
`breast cancer (MBC) previously treated with trastuzumab (T) and a taxane. Program and abstracts of the
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`American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012; Chicago, Illinois.
`Abstract LBA1.
`
`2. Rugo HS, Barry WT, Morena-Aspitia A, et al. CALGB 40502/NCCTG N063H: randomized phase III trial of
`weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix)
`with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC).
`Program and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June
`1-5, 2012; Chicago, Illinois. Abstract CRA1002.
`
`3. Schneider BP, Wang M, Radovich M, et al; ECOG 2100. Association of vascular endothelial growth factor
`and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel
`compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J Clin Oncol.
`2008;26:4672-4678. Abstract
`
`4.
`
`Im YH, Park YH, Jung KH, et al. A phase III, multicenter, randomized trial of maintenance versus observation
`after achieving clinical response in patients with metastatic breast cancer who received six cycles of
`gemcitabine plus paclitaxel as first-line chemotherapy (KCSG-BR 0702, NCT00561119). Program and
`abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012;
`Chicago, Illinois. Abstract 1003.
`
`5. Swain SM, Tang G, Geyer CE, et al. NSABP B-38: definitive analysis of a randomized adjuvant trial
`comparing dose-dense (DD) AC ¨paclitaxel (P) plus gemcitabine (G) with DD AC ¨P and with docetaxel,
`doxorubicin, and cyclophosphamide (TAC) in women with operable, node-positive breast cancer. Program
`and abstracts of the American Society of Clinical Oncology Annual Meeting and Exposition; June 1-5, 2012;
`Chicago, Illinois. Abstract LBA1000.
`
`6. Marin M, Lluch A, Ruiz A, et al. Randomized phase III study of adjuvant chemotherapy for high-risk, node-
`negative breast cancer (BC) comparing FAC with FAC followed by weekly paclitaxel: First efficacy analysis of
`the GEICAM/2003-02 trial. Program and abstracts of the American Society of Clinical Oncology Annual
`Meeting and Exposition; June 1-5, 2012; Chicago, Illinois. Abstract 1001.
`
`7. Gnant M, Mlineritsch B, Schippinger W, et al; ABCSG-12 Trial Investigators, Marth C. Endocrine therapy plus
`zoledronic acid in premenopausal breast cancer. N Engl J Med 2009; 360:679-691.
`
`8. Coleman RE, Marshall H, Cameron D, et al; AZURE Investigators. Breast-cancer adjuvant therapy with
`zoledronic acid. N Engl J Med. 2011;365:1396-1405. Abstract
`
`Medscape Oncology © 2012 WebMD, LLC
`
`Cite this article: Kathy D. Miller, Harold J. Burstein. T-DM1: Golden Age in HER2+ Breast
`Cancer? Medscape. Jun 12, 2012.
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`http://www.medscape.com/viewarticle/765248_print
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`T-DM1: Golden Age in HER2+ Breast Cancer?
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`Authors and Disclosures
`
`Author(s)
`
`Kathy D. Miller, MD
`
`Associate Professor of Medicine, Indiana University School of Medicine; Breast Oncologist, Indiana University Simon Cancer Center, Indianapolis, Indiana
`
`Disclosure: Kathy D. Miller, MD, has disclosed the following relevant financial relationships:
`
`Served as a speaker or member of a speakers bureau for: Genentech, Inc.; Roche
`
`Received income in an amount equal to or greater than $250 from: Genentech, Inc.; Bristol-Myers Squibb Company; AstraZeneca Pharmaceuticals LP; Roche; Clovis Oncology
`
`Associate Professor, Harvard Medical School; Medical Oncologist, Dana-Farber Cancer Institute, Boston, Massachusetts
`
`Harold J. Burstein, MD, PhD
`
`Disclosure: Harold J. Burstein, MD, PhD, has disclosed no relevant financial relationships.
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